Halogen-aminocarbonyloxy compounds of the steroid series

ABSTRACT

VICINAL HALOGEN-AMINOCARBONYLOXY COMPOUNDS OF THE STEROID SERIES, IN WHICH THE AMINO GROUP CAN BE SUBSTITUTED OR UNSUBSTITUTED, HAVING THE FORMULA   X-C(&lt;)-C(&lt;)-O-CO-NH-R   WHEREIN C-C DESIGNATES A SEGMENT OF THE STEROID FRAMEWORK, X DESIGNATES HALOGEN, AND R DESIGNATES HYDROGEN, AN ALKYL, ARYL, ARYLALKYL, CYCLOHEXYL, UNSUBSTITUTED OR SUBSTITUTED AMINO GROUP OR ACID GROUP AND A PROCESS OF PREPARING THIS CLASS OF COMPOUNDS COMPRISING REACTING A CIS- OR TRANS-HALOGEN-HYDRINE OF THE STEROID SERIES WITH PHOSGENE IN AN INERT SOLVENT UNDER ADDITION OF A BASIC CATALYST TO FORM THE CORRESPONDING CHLOROCARBONIC ACID ESTER, REACTING THE LATTER WITH AN NH-ACTIVE COMPOUND IN A SOLVENT UNDER ADDITION OF AN ACID BINDING AGENT, THE REACTION BEING FACILITATED WHERE NECESSARY BY ADDITION OF A TERTIARY AMINE. THE STEROIDS OF THE INVENTION ARE CHARACTERIZED BY THEIR OUTSTANDING PHARMACOLOGICAL ACTIVITY.

United States Patent Olfice 3,663,580 HALOGEN-AMINOCARBONYLOXY COMPOUNDS OF THE STEROID SERIES Kurt Ponsold and Peter Grosse, Jena, Germany, assignors to VEB Jena Pharm, Jena, Germany No Drawing. Filed Mar. 6, 1970, Ser. No. 17,325 Int. Cl. C07c 169/20, 169/60 US. Cl. 260397.2 24 Claims ABSTRACT OF THE DISCLOSURE Vicinal halogen-aminocarbonyloxy compounds of the steroid series, in which the amino group can be substituted or unsubstituted, having the formula --X O -(:3-O- NHR wherein C-C designates a segment of the steroid framework, X designates halogen, and R designates hydrogen, an alkyl, aryl, arylalkyl, cyclohexyl, unsubstituted or sub stituted amino group or acid group and a process of preparing this class of compounds comprising reacting a cisor trans-halogen-hydrine of the steroid series with phosgene in an inert solvent under addition of a basic catalyst to form the corresponding chlorocarbonic acid ester, reacting the latter with an NH-active compound in a solvent under addition of an acid binding agent, the reaction being facilitated where necessary by addition of a tertiary amine.

The steroids of the invention are characterized by their outstanding pharmacological activity.

This invention relates to a novel class of vicinal halogen-aminocarbonyloxy compounds of the steroid series and to a process of preparing such compounds. Moreparticularly this invention relates to vicinal halogenaminocarbonyloxy compounds of the steroid series in which the amino group can be substituted or unsubstituted having the formula wherein C-C designates a segment of the steroid framework, X designates halogen, and R designates hydrogen, an alkyl, aryl, arylalkyl, cyclohexyl, unsubstituted or substituted amino group or acid group and to a process of preparing such compounds.

It is already known to prepare N-substituted aminocarbonyloxy compounds by reacting a hydroxyl group containing compound with phosgene to form a chlorocarbonic acid ester and thereafter reacting the ester with an NH-active compound. It is also known in the art to react simple steroid alcohols with phosgene to form the corresponding chlorocarbonic acid esters. The reaction of vicinal steroid-halogen-hydrine with phosgene following which the chlorocarbonic acid ester thereby obtained is reacted with an amine to form the vicinal N-substituted halogen-aminocarbonyloxy compound has not, however, as yet been described.

The reaction of steroid alcohols with isocyanates to form aminocarbonyloxy compounds is also known. The preparation of vicinal halogen-aminocarbonyloxy steroids from steroidal halogen hydrines through reaction with isocyanates has, on the other hand, not as yet been described.

The invention lies in the surprising finding that vicinal N-su-bstituted or N-unsubstituted halogen-aminocarbonyloxy steroids can easily be prepared from readily available halogen hydrines of the steroid series. According to the invention, vicinal halogen-aminocarbonyloxy compounds of the steroid series are prepared by reacting a cisor trans-steroid halogen hydrine with phosgene in an inert solvent, as, for instance, benzene, under addition of a basic catalyst, thereafter reacting the thus formed chlorocarbonic acid ester with an NH-active compound in a suitable solvent under addition of an acid binding agent, and possibly in the presence of a tertiary amine. Instances of suitable solvents are ethanol, tetrahydrofuran and acetone. As NH-active compound there may be suitably used amines, hydrazines, substituted hydrazines, amides, amino acids or their carboxyl derivatives. By the addition of a sufiiciently strong basic compound in a suitable amount, the NH-active compound can also be used in the form of its generally more readily handled salt. For the process of the invention, it is immaterial whether the chlorocarboxylic acid ester separated from the excess phosgene is purified or is further used as the crude prodnet.

It has also been found in accordance with the invention, that cisor trans-steroid halogen hydrines can be reacted with alkyl or aryl substituted isocyanates or with cyanic acid in an inert solvent under elevated temperatures and under addition of a basic catalyst to form the corresponding vicinal halogen-aminocarbonyloxy compound. It has further been found in accordance with the invention that by using alkali cyanates, the free necessary cyanic acid can be obtained during the reaction conducted in an inert solvent by the addition of trifiuoracetic acid.

In accordance with the invention, per mol of steroid chlorocarbonic acid ester, 1 to 10 mol, preferably 2.5 mol NH active compound are used while per mol steroid halogen-hydrine, 225 mols, preferably 5 to 6 mols isocyanate are reacted.

The halogen-aminocarbonyloxy compounds of the steroid series prepared in accordance with the invention are characterized by their pharmacological activity, the same being derived from the steroid portion of the molecule. The compounds of the invention have been found to possess excellent estrogenic and antigonatropic activity. They may be administered orally or parenterally. Preferably, they are utilized in tablet or capsule form. In addition, the compounds of the invention have been found to constitute highly desirable starting materials for future syntheses.

The invention will be further illustrated by the following examples; however the same are not to be construed in anywise limiting the same.

EXAMPLE 1 16 a-bromo-3-methoxy-estra- 1 ,3,5 10) -triene- 1713-01- chlorocarbonic acid ester 500 mg. 16a-br0mo-3-methoxy-estra-1,3,5(1O)-triene- 1713-01 were dissolved in 11 ml. benzene phosgene solution (about 250 mg. phosgene per ml). Following cooling of the resultant solution to about 0 C., 0.2 ml. triethylamine in 1.3 to 1.5 ml. benzene were slowly added thereto. The reaction mixture was allowed to stand overnight at room temperature. It was thereafter filtered and concentrated under vacuum. The resultant oily, slowly crystallizing product was used without further purification for further reaction.

M.P. 1161l9 C. Analytical M.P. -132 C.

EXAMPLE 2 16a-bromo-17B-cyclohexylaminocarbonyloxy-estra- 1,3,5 (10)-triene-3-methyl ether Using the procedure of Example 1, from 500 mg. 1600- bromo-3-methoxy-estra-l,3,5(10)-triene-17/3-ol, the chlorocarbonic acid ester was prepared. The ester was dissolved in 2025 ml. acetone and under ice cooling reacted with 1 ml. cyclohexylamine. The reaction mixture was allowed to stand in an ice bath for 1 hour and then poured into water. The precipitated product was separated off with suction. The recovered product could be crystallized out of methanol.

M.P. 155l58 C. [u] =|-21 (c.=1, CHClg).

EXAMPLE 3 17B-ethylenaminocarbonyloxy-1 6a-bromo-estra- 1,3,5 (10)-triene-3 methylether The chloro-carbonic ester which was prepared, according to the procedure of Example 1, from 500 mg. 1611- bromo-3-methoxy-estra-1,3,5(IO-triene 17/8 01 was dissolved in 20 to 25 ml. acetone and under ice cooling reacted with 2 ml. ethylamine. After standing for 1 hour in an icebath, the reaction mixture was poured into water and extracted with benzene. Following drying and concentration, there was recovered an oil which could be crystallized out of methanol.

EXAMPLE 4 17,6-benzylaminocarbonyloxy-16a-bromo-estra- 1,3,5 10)-triene-3-methylether The chloro-carbonie acid ester prepared from 500 mg. 16a-bromo-3-methoxy-estra-1,3,5 10) -triene-17;8-ol by the procedure set out in Example 1 was dissolved in 20-25 ml. acetone and reacted with 1 ml. benzylamine, under ice cooling. The reaction mixture was allowed to stand for 1 hour in an icebath and Was then poured into water and extracted with benzene. After drying and concentration, there was recovered a yellow oil which could be crystallized out of methanol.

M.P.: 160.5-163" C.

EXAMPLE 5 17fl-anilinocarbonyloxy-16a-bromo-estra-1,3,5(10)- triene-3-methylether Following the procedure of Example 1, the chloro carbonic acid ester was prepare dfrom 500 mg. 160:- bromo-3-methoxy-estra-1,3,5 -triene-17;3-ol. The ester was dissolved in 20 to 25 ml. acetone and reacted with 1 ml. aniline under ice cooling. After standing for 1 hour in an icebath the reaction mixture was poured into water and extracted with benzene. Following drying and concentration, there was recovered an oil which was crystallized out of benzene-benzine (B.P., 5060 C.).

M.P. 180-182 C. [a] =-17 (c.=1, CHCl EXAMPLE 6 l7fl-anilinocarbonyloxy-16p-chloro-estra-1,3,5 l0) triene-3-methylether Using the procedure set out in Example 1, the chlorocarbonic acid ester was prepared from 500 mg. 16 8-chlo ro-3-methoxy-estra-l,3,5(10)-triene-17,B-ol. The ester was dissolved in 20-25 ml. acetone and under ice cooling reacted with 1 ml. aniline. After standing in ice water for 1 hour, the reaction mixture was poured into water and extracted with benzene. Following drying and concentration in vacuum, a colorless, chromatographically pure, amorphous product was recovered.

EXAMPLE 7 l6u-bromo-17fi-hydrazinocarbonyloxy-estra-l,3,5 10 triene-S-methylether The chloro-carbonic acid ester, prepared by the procedure set out in Example 1, from 500 mg. 16a-bromo-3- methoxy-estra-1,3,5(10)-triene-17B-ol, was dissolved in ml. absolute ethanol and 5 m1. tetrahydro-furan and under ice cooling reacted with 0.6 ml. 98% hydrazine hydrate. After standing for 1 hour in an icebath, the reaction mixture was poured into aqueous sodium chloride solution and the precipitated product thereby formed sep arated off with suction. The purification of the product was carried out by chromatography on silica gel whereby the main impurities were separated oif from the desired methylether. The elution was carried out first with benzene-ether (10:1), followed by benzene-methanol (10:1). The product was thereafter crystallized from methanolwater.

M.P.: 146l49 C.

EXAMPLE 8 16et-bromo-17/3-isopropylidene hydrazino-carbonyloxyestral 3,5 10) -triene-3 -methylether According to the procedure of Example 1, the chlorocarbonic acid ester was prepared from 500 mg. 16oc-br0- mo-3-methoxy-estra-1,3,5(10)-triene 175 01. The ester was dissolved in 20 ml. acetone and under ice cooling reacted with 0.6 ml. 98% hydrazine hydrate. Following standing for 1 hour in an icebath, the reaction mixture was poured into water or aqueous sodium chloride solution and the product which was thereby separated out, taken off by suction filtering. The purification was carried out by chromatographing on silica gel. Benzene-acetone (:1) served to elute the main impurities, benzene-acetone (40:1), a weaker impurity and thereafter the desired methyl ether. Crystallization was carried out from acetonewater.

M.P.: 153-l56 C.

EXAMPLE 9 16a-bromo-l7 3-N,N-dimethylhydrazino-carbonyloxyestra- 1,3 ,5 10 -trienefi3-methylether The procedure of Example 1 was followed to prepare the chloro-carbonic acid ester from 500 mg. 1'6a-bromo- 3-methoxy-estra-1,3,5(10)-triene-17B-ol. The ester was then dissolved in 15 ml. absolute ethanol and 5 ml. absolute tetrahydrofuran and under ice cooling reacted with 1 ml. N,N-dimethylhydrazine, and thereafter 0.1 ml. triethylamine was introduced into the reaction mixture. Following pouring into water and standing for 1 hour, the precipitated product was separated off with suction. Purification was carried out through chromatographing on silica gel with benzene-ether (10:1). The main impurities were eluted off in the first fractions and the impurity free desired methylether then recovered. Crystallization from methanol-water followed.

M.P.: 179-182 C.

EXAMPLE 1O 17B-ethoxycarbonylmethylaminocarbonyloxy-16abromo-estra-1,3,5 10)-triene-3-methylether The chloro-carbonic acid ester prepared from 500 mg. 16u-bromo-3-methoxy-estra 1,3,5(10) -triene-17fi-ol by the procedure of Example 1, was dissolved in 2 ml. acetone. 700 mg. glycocollethylester-hydrochloride were introduced into this solution and then under stirring and cooling, 0.8 ml. triethylamine in 5 ml. acetone were added in dropwise fashion. After 2 hours, the reaction mixture was poured into water and the resultant emulsion extracted with ether. Following drying and concentration, there was recovered a slowly crystallizing oil, which could be recrystallized out of methanol.

M.P.: 155-158 C.

EXAMPLE l1 17fl-acetamidocarbonyloxy-16a-bromo-estra- 1,3,5 10)-triene-3-methylether The chlorocarbonic acid ester prepared by the procedure of Example 1, from 500 mg. 16a-bromo-3-methoxy-estra-1,3,5(10)-triene-17B-ol was dissolved in 20 ml. acetone and reacted with 300 mg. acetamide. Following theaddition of, 0.5 ml. triethylamine, the reaction mixture was stirred for 3 hours at roomtemperature and then poured into water. Following extraction with ether and drying, the ether solution was concentrated. The

thusly recovered semi-solid product was purified bychromatographing on silica gel (elution agent-benzene).

M.P.: 117-120 C. (petroleum ether).

EXAMPLE 12 4 2,8-chloro-3 a-phenylcarbamyloxy-androstane-17-one 1 g. Zfl-chloro-androstane-17-one-3oi-ol in 12 ml. absolute toluene was heated under reflux with 1.5 ml. phenylisocyanate and 5 ,drops triethylamine, for 8 to 10 hours. The solution was concentrated in vacuum until the odor of= phenylisocyanate was no longer apparent. The semisolid product was chromatographed over 20 g. aluminum agent. The yield oxide S III with benzene as the eluting amounted to 1.25 g. (90%)..

M.P.: 185.5 to 187.5 C. (metha o1); [a] ;+93.7 (c.=l, CHCls). r EXAMPLE 13 2a-bromo-3fi-ethylcarbamyloxy-cholestane 2a-bromo-3B-carbamyloxy-cholestane 2.4 g. 2u-bromocholestane-3fl-ol and 2.6 g. sodium cyanate were stirred together in 20 ml. benzene. Thereafter, over a period of 1 minute, 3.1 ml. tri'fluoroacetic acid were dropped in and the resulting mixture stirred for a further 3 hours. Following standing overnight, the mixture was mixed with water, the benzene layer separated off, the aqueous phase again extracted with benzene and the impurity containing benzene extract washed with water. Following drying over Na SO the extract was concentrated in vacuum and crystallized out of absolute alcohol. The yield amounted to 1.6 g. (61% of theory).

M.P. 203-204.5 C. (absolute ethanol).

(c.=1.l, CHC1 EXAMPLE 15 3-methoxy-16ot-bromo-l7u phenylcarbamyloxyestra 1,3,5 (10)-triene 1.8 g. 3-methoxy-1'6a-bromo-estra-1,3,5(10)-triene- 1711-01, 3. 6 ml. phenyl-isocyanate and 10-12 drops triethylamine in m1. absolute toluene were maintained at boiling for 15 hours. Following cooling, filtering, concentration in vacuum and chromatographing with benzene over 30 g. A1 0 SUI (about 800 ml. eluate). The yield amounted to 2.1 g. (93% of theory).

M.P.: 1665-16 8.? C. (methanol/water).

EXAMPLE 16 2a-bromo-3fl-phenylcarbamyloxy-cholestane 1 g. 2a-bromocholestane-343-01 and 0.8 ml. phenylisocyanate in 10 ml. toluene were heated under reflux for '6 hours. Following concentration in vacuum, until the odor of phenylisocyanate was no longer apparent, the product was crystallized out of alcohol or methyl-glycol. The yield amounted to 975 mg. (77%).

M.P.: 167.5-168.5 C. (methylglycol). [u] =-32. (c.=l, CHCl EXAMPLE 17 17fl-aminocarbonyloxy-16a-b'romo-estral,3,5 10) triene-methylether 1.9 g. 16ix-bromo-3 -methoxy-estra-1,3,5(10)-triene- 175-01 were reacted with sodium cyanate and trifluoroacetic acid according to the procedure of Example 14. The recovered crude product was purified by chromatography on silica gel.

M.P.: 225-228" (c.=0.45; CHC1 EXAMPLE 1'8 16a-bromo-17fl-(a-naphthyylamino)-carbony1oxy- 1,3,5 10) -1-triene-3-methylether l g. of l6a-tbromo-33methoxy-e-stra-1,3,5 (l0).triene- 175-01 was converted into the chlorocarbonic acid ester analogouslyto the procedure of Example 1 and then reacted with 1 -naphthylamin'e andf800 mg. K CO in 40 ml; acetone while stirring for four hours at room temperature. Following the addition of water to the reac tion mixture, the reaction mixture was extracted with ether, the extract washed with dilute sulfuric acid, dried and evaporated. The crude product thereby recovered was purified by preparative layer chromatography on aluminum oxide (acid, activated substance I) with benzeneacetone as eluting agent.

C. (abs. ethanol) [a] :+30

EXAMPLE 19 16a-bomo-17/3-(N-phenylhydrazine) carbonyloxyestra-1,3,5 10) -triene-3-methylether Following the procedure of Example 1, 1 g. of bromo-3-methoxy-estra-1,3,5(10)-triene-17fl-ol was convcrtcd into the chlorocarbonic acid ester. The ester was dissolved in 20 ml. abs. THE/20 ml. abs. ethanol and under ice cooling aod stirring reacted with 1 ml. phenylhydrazine. Following stirring for a further hour, water was added to the reaction mixture and it was then extracted with ether. The crude product was precipitated out of benzene/benzine and recrystallized from methanol/water.

M.P.: 1-68-173 C. (methanol/water). [a] 2+18 (c.=0.5; OHCl EXAMPLE 20 l6u-bromo-17,9 (N-tosylhydrazino) carbonyloxy-estra- 1,3,5( 10)-triene-3-methylether l g. 16a-bromo-3-methoxy-estra-1,3,5(10)-triene-17B-ol was converted into the chlorocarbonic acid ester according to Example 1, and the ester together with 1.2 g. ptosylhydrazide stirred for 2 hours in 20 ml. THE/ethanol. After dilution with water and ether extraction, a crude product was recovered which was purified by chromatographing on silica gel with benzene/ether (40:1 increasing to 20:1).

M.P.: -173 C. (methanol/water). [a] :+12 (c.=0.4 CHCl EXAMPLE 21 16a-bromo-l7p-tosylaminocarbonyl-oxy-estra-1,3,5(10)- triene-3-methyl-ether C. (methanol/ water. M1 +6 7 ly basic NH-active compounds are employed as reaction components (see Examples .2-8), no acid binding agent is required as the excess of these NH-active compounds serve for this purpose. It is further possible to use as acid binding agent, metal carbonates such as K CO Included among the suitable NH-active compounds are the following: cyclohexylamine, cthylamine, benzylamine, aniline, hydrazines-hydrate, N,N-dimethylhydrazine, glycocol-ethyl-ester hydrochloride, acetamide, phenylhydrazine, a-naphthylamine and tosylhydrazine.

Illustrative starting steroids include 16u-b1'0m0-3- methoxy-estra-1,3 ,5( 10) -triene-17fi-ol, 2,8-chloro-androstame-17 one-3a-bromo-cholestane-3/3-ol, 3-methoxy-l6abromoestra-l,3,5(10)-triene-l7a-01.

We claim:

1. A vicinal halogenaminocarbonyloxy compound of the steroid series having a formula, selected from' and wherein X designates halogen, R designates hydrogen, alkyl, aryl, aralkyl and cyclohexyl, unsubstituted monoor di-substituted amino or an acid group and R designates oxygen 5. A compound according to claim 1 designated 175- benzylaminocarbonyloxyl 6u-bromoestra 1,'3,5( )-triene-3-methy1 ether.

6. A compound according to claim 1 designated 17,8- anilino-carbonyloxy 16a bromo-estra-1,3,5(10)-triene- 3-methyl ether.

7. A compound according to claim 1 designated 17;??- anilinocarbonyloxy 165 chloro-estra-1,3,5(10)-triene- B-methyl ether. I

8. A compound according to claim 1 designated 1 6 0:- bromo 17B hydrazinocarbonyloxy-estra-1,3,5(10)-trienc-3-methyl ether. H

9. A compound according to claim 1 designated 16o:- -bromo 175 isopropylidenehydrazino-carbonyloxy-estra- 1,3,5 (10)-triene-3-methyl-ether. p v

10. A compound according to claim 1 designated 16ebromo 17 ,8 N,N-dimethylhydrazinocarbonyl-oxy estra- 1,3,5 (10)-triene-3-methy1 ether. Q

11. A compound according to claim 1 designated 17;?- ethoxycarbonylmethylaminocarbonyloxy 16a bromoestra-l,3,5( 10)-triehe-3-methyl ether. '7 i 12. A compound according to claim 1 designated 1 7B- acetamido-carbonyloxy 16a ene-3-methyl ether. i

'13. A compound according to claim '1 designatedZB- chloro-3cuphenylcarbamyloxy-androstane-17-one.

'14. A compound according to claim 1 designated 20;- bromo'3B-ethylcarbamyloxy-cholestane.

15. A compound according to claim 1 designated 2abromo-3B-carbamyloxy-cholestane.

16. A compound according to claim 1 designated 3- methoxy --16oz bromo 17m phenylcarbamyloxy-estral,3,5(10)-triene.

17. A compound according to claim 1 designated 2abromo-3fl-phenylcarbamyloxy-cholestane.

Process of preparing a compound according to claim 1 which comprises reacting a cisor trans-halogen hydrin of the steroid series having a formula selected from bromo-estra-'1',3,5(10)-triand with phos'gene in an inert solvent'in the presence of a basic catalyst and thereafter reacting the chlorocarbonic acid ester of the steroid thereby formed with 1 to ID mol NH-active compound selected from the group consisting of alkylamines arylamines, ar'alkylamines, cyclohexylamine, unsubstituted, rnonoor disubstituted hydrazine or an amide in a solvent at temperature not exceeding room temperature and under addition of an acid binding agent.

19. Process according to claim 18 wherein said NH- active compound is used in the form of its salt and is freed in. situ by addition of astrongly basic compound.

20. Process ofpreparing a compound according to claim 1 wherein R designates. hydrogen, alkyl or aryl which comprisesreacting cistrans-steroid halogenhydrin having a formula selected from wherein X designates halogen andRydesignates oxygen or H I h t} with 2 to 25 -mols, of an-alk ylor ar yl-isocyanat e or with free cyanic acid at an elevated temperature in an inert solvent, in the presence of a tertiary amine as catalyst.

9 10 21. Process according to claim 20 wherein the free cy- References Cited zfigcieagildi ifglrlrgireiiiriircinagcitie reaction from sodium cy- UNITED STATES PATENTS P t 18, h b 3,153,065 10/1964 Bowers et a1 260-39745 mess mg 0 mm W cm S 1 3,169,137 2/1965 Wendt et a1 260-3975 catalyst is triethylamine. 5

2 3. Process according to claim 18 wherem Sflld NH- ELBERT L. ROBERTSPrimary Examiner active compound is used in an amount of 2.5 mols.

24. Process according to claim 18 wherein said acid US Cl. binding agent is a member selected from the group of trialkylamine, tertiary amines and metal carbonates. 10 260 397-4 397-5 

